Project 1 is focused on the virology of CNS infection as sampled in the CSF. We have recently identified macrophage-tropic virus in the CSF of a subset of subjects diagnosed with HIV-associated dementia. In another subset of HAD subjects we identified CSF-compartmentalized HIV that had an entry phenotype that required high concentrations of CD4 indicative of infection of activated T cells, and this was associated with pleocytosis. Thus, CNS infection can occur through two distinct pathways, infection of T cells presumably drawn into the CNS by concurrent inflammation, or infection of long-lived macrophage/microglia cells. We have also detected both types of viruses as compartmentalized variants in non-demented subjects. We propose to analyze the extent of compartmentalization and tropism in subjects entering therapy. This will be part of a comprehensive analysis of Inflammation, neuronal damage, and neuropsychiatric evaluation at entry and during the first year of therapy (Project 2). In addition, this information will be used in the context of persistent CNS infection in the face of successful treatment (Project 3). We hypothesize that knowledge about the nature of CNS infection will be important to understanding the complex of symptoms known as HAND, and that this knowledge will ultimately contribute to a mechanism-based intervention that will reverse and alleviate its effects.